Alternative synthesis of renin inhibitors and intermediates thereof

ABSTRACT

The present invention relates to synthetic routes to prepare a compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein R 1  is halogen, C 1-6 halogenalkyl, C 1-6 alkoxy-C 1-6 alkyloxy or C 1-6 alkoxy-C 1-6 alkyl; R 2  is halogen, C 1-4 alkyl or C 1-4 alkoxy; R 3  and R 4  are independently branched C 3-6 alkyl; and R 5  is cycloalkyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkanoyloxy-C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkylamino-C 1-6 alkyl, C 1-6 dialkylamino-C 1-6 alkyl, C 1-6 alkanoylamino-C 1-6 alkyl, HO(O)C-C 1-6 alkyl, C 1-6 alkyl-O—(O)C—C 1-6 alkyl, H 2 N—C(O)—C 1-6 alkyl, C 1-6 alkyl-HN—C(O)—C 1-6 alkyl or (C 1-6 alkyl) 2 N—C(O)—C 1-6 alkyl; or a pharmaceutically acceptable salt thereof as well as key intermediates obtained when following these routes as well as their preparation.

The present invention provides methods for preparing certain2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amidederivatives, or pharmaceutically acceptable salts thereof. The presentinvention further relates to novel intermediates useful in themanufacture of the same.

More specifically, the2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amidederivatives to which the methods of the present invention applies areany of those having renin inhibitory activity and, therefore,pharmaceutical utility, e.g., those disclosed in U.S. Pat. No.5,559,111.

Surprisingly, it has now been found that2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amidederivatives are obtainable in high diastereomeric and enantiomericpurity using pyro-glutamic acid, in particular, L-pyro-glutamic acid, asthe starting material.

In particular, the present invention provides a method for thepreparation of a compound of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl; R₂ is halogen, C₁₋₄alkyl or C₁₋₄alkoxy; R₃ and R₄are independently branched C₃₋₆alkyl; and R₅ is cycloalkyl, C₁₋₆alkyl,C₁₋₆hydroxyalkyl, C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆alkanoyloxy-C₁₋₆alkyl,C₁₋₆aminoalkyl, C₁₋₆alkylamino-C₁₋₆alkyl, C₁₋₆dialkylamino-C₁₋₆alkyl,C₁₋₆alkanoylamino-C₁₋₆alkyl, HO(O)C—C₁₋₆alkyl,C₁₋₆alkyl-O—(O)C—C₁₋₆alkyl, H₂N—C(O)—C₁₋₆alkyl,C₁₋₆alkyl-HN—C(O)—C₁₋₆alkyl or (C₁₋₆alkyl)₂N—C(O)—C₁₋₆alkyl; or apharmaceutically acceptable salt thereof; which method comprisesstarting from L-pyro-glutamic acid and following reaction steps asoutlined in Scheme 1a.

Compound (IV) can be prepared from from L-pyro-glutamic acid via theunprotected 5-hydroxymethyl-3-substituted isopropyl pyrrolidinone (III)as shown in the first steps of Schemes 1b and 1.

Thus, the present invention provides also a method for the preparationof a compound of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl; R₂ is halogen, C₁₋₄alkyl or C₁₋₄alkoxy; R₃ and R₄are independently branched C₃₋₆alkyl; and R₅ is cycloalkyl, C₁₋₆alkyl,C₁₋₆hydroxyalkyl, C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆alkanoyloxy-C₁₋₆alkyl,C₁₋₆aminoalkyl, C₁₋₆alkylamino-C₁₋₆alkyl, C₁₋₆dialkylamino-C₁₋₆alkyl,C₁₋₆alkanoylamino-C₁₋₆alkyl, HO(O)C—C₁₋₆alkyl,C₁₋₆alkyl-O—(O)C—C₁₋₆alkyl, H₂N—C(O)—C₁₋₆alkyl,C₁₋₆alkyl-HN—C(O)—C₁₋₆alkyl or (C₁₋₆alkyl)₂N—C(O)—C₁₋₆alkyl; or apharmaceutically acceptable salt thereof; which method comprisesstarting from L-pyro-glutamic acid and following reaction steps asoutlined in Scheme 1b.

The present invention provides also a method for the preparation of acompound of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl; R₂ is halogen, C₁₋₄alkyl or C₁₋₄alkoxy; R₃ and R₄are independently branched C₃₋₆alkyl; and R₅ is cycloalkyl, C₁₋₆alkyl,C₁₋₆hydroxyalkyl, C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆alkanoyloxy-C₁₋₆alkyl,C₁₋₆aminoalkyl, C₁₋₆alkylamino-C₁₋₆alkyl, C₁₋₆dialkylamino-C₁₋₆alkyl,C₁₋₆alkanoylamino-C₁₋₆alkyl, HO(O)C—C₁₋₆alkyl,C₁₋₆alkyl-O—(O)C—C₁₋₆alkyl, H₂N—C(O)—C₁₋₆alkyl,C₁₋₆alkyl-HN—C(O)—C₁₋₆alkyl or (C₁₋₆alkyl)₂N—C(O)—C₁₋₆alkyl; or apharmaceutically acceptable salt thereof; which method comprisesstarting from L-pyro-glutamic acid and following reaction steps asoutlined in Scheme 1.

In each of the schemes the variants have the same meaning as set forthfor the compounds of formula (A) or as explained below.

Compounds of formula (III), wherein R₃ has meaning as defined forformula (A), are key intermediates in the methods of the presentinvention having the desired stereochemistry already at place at carbonscorresponding to position 5 and 7 in the compounds of formula (A).

As illustrated in Schemes 1b and 1, compounds of formula (III) whereinR3 has meaning as defined herein above, may be obtained starting byesterification of L-pyro-glutamic acid according to methods illustratedherein in the Examples, or using methods well known in the art, toafford compounds of formula (II) wherein R₆ is C₁₋₂₀alkyl,C₃₋₁₂cycloalkyl, C₃₋₁₂cycloalkyl-C₁₋₆alkyl, C₆₋₁₀aryl orC₆₋₁₀aryl-C₁₋₆alkyl, more preferably C₁₋₆alkyl, still more preferablyC₁₋₄alkyl, most preferably methyl or ethyl. Compounds of formula (II)may then be converted to compounds of formula (III) following thereaction steps as exemplified below in Scheme 2.

a) According to Scheme 2 Compound (II), wherein R₆ has meanings asdefined herein, is reduced to afford the corresponding alcohol (IIa).The reduction is typically conducted with a complex borohydride likeLiBH₄ or NaBH₄ in the presence of LiCl in an appropriate solvent likeTHF, etc. a mixture of THF and an alcohol as for example EtOH, i-PrOH,etc. to compound (IIa) as known from literature. Reference is made to1a) M. Moloney et al., Tetrahedron, 52, (10) 3719 (1996)

b) Compound (IIa) is acetalized with an aromatic aldehyde to yieldcompound of formula (IIb), wherein the phenyl ring shown in thestructure may be substituted by one or more, e.g. two or three, residuese.g. those selected from the group consisting of C₁-C₇-alkyl, hydroxy,C₁-C₇-alkoxy, C₂-C₈-alkanoyl-oxy, halogen, nitro, cyano, and CF₃.Acetalization of compound of formula (IIa) is preferably performed withbenzaldehyde or another aromatic aldehyde according to literatureprocedures to compound (IIb). Reference is made to 2a) M. Moloney etal., Tetrahedron: Asymmetry, 6, 337 (1995); 2b) M. Moloney et al.,Tetrahedron, 52, (10) 3719 (1996).

c) Compound (IIb) is activated by a carboalkoxylation followed byalkylation with an electrophile R₃—X, wherein X is a leaving group, e.g. halogen or sulfonyloxy and R₃ is as defined hererin, to obtaincompound of formula (IIc), wherein the phenyl ring shown in thestructure may be substituted by one or more, e.g. two or three, residuese.g. those selected from the group consisting of C₁-C₇-alkyl, hydroxy,C₁-C₇-alkoxy, C₂-C₈-alkanoyl-oxy, halogen, nitro, cyano, and CF₃.Preferably, activation proceeds via a carboalkoxylation, e.g. acarbomethoxylation or carboethoxylation, mediated by treatment of (IIb)with e.g. NaH in THF or mixture of THF/DMF followed by a electrophilelike a carbonate or a phosgene derivative like Cl—CO—OR₆. R₆ is asdefined herein, preferably C₁₋₆alkyl, more preferably C₁₋₄alkyl, mostpreferably methyl or ethyl. This intermediate is then deprotonated andafterwards alkylated with an electrophile like R₃—X, wherein R₃ is asdefined herein, as described in e.g. M. Moloney et al., Tetrahedron, 52,(10) 3719 (1996) to obtain compound (IIc), Especially alkylating suchcarboalkoxy activated intermediates with branched, secondary alkylatingagents like R—C—X—R′ is preferred. Leaving groups X can be halogen,sulfonyloxy, etc.

d) Compounds (IIc) are saponified at the ester group followed bydecarboxylation to yield compound of formula (IId), wherein the phenylring shown in the structure may be substituted by one or more, e.g. twoor three, residues e.g. those selected from the group consisting ofC₁-C₇-alkyl, hydroxy, C₁-C₇-alkoxy, C₂-C₈-alkanoyl-oxy, halogen, nitro,cyano, and CF₃, and R₃ is as defined herein. Saponification of compoundof formula (IIc) proceeds preferably with aqueous base (NaOH) at theester group, and then it is acidified and decarboxylated to compounds(IId), which can be destilled in some cases. Reference is made to theliterature methods of 2b), above.

e) Compounds (IId) are deacetalised or transacetalised to yield compoundof formula (III), wherein and R₃ is as defined herein. Deacetalizationor transacetalization preferably proceeds by treatment with anhydrousacid like CF₃COOH, HCl in toluene or dioxane, or by acid catalysedtransacetalisation in the presence of an alcohol to give compounds(III). Reference is made to the literature methods of 2b) above.

Compounds of formula (III) wherein R₃ has meaning as defined hereinabove, may then be converted to compounds of formula (IV) wherein R₇ isO-protecting group such as C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy,C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₀aryl-C₁₋₆alkoxycarbonylor (C₁₋₈alkyl)₃silyl; and R₈ is N-protecting group such asC₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl, C₆₋₁₀aryl-carbonyl,C₁₋₆alkoxy-carbonyl, C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl; by simultaneous orsequential protection of the hydroxyl and the amino group depending onthe nature of R₇ and R₈. This is typically performed using standardprotecting group chemistry following the procedures as described in theliterature referenced below.

As an alternative to the first steps outlined in Scheme 1, the compoundof formula (IV) can be prepared from the compound of formula (I) shownin Scheme 1 via the route outlined in Scheme 1c.

The esterification of the compound of formula (I) typically proceedsaccording to methods illustrated herein in the Examples, or usingmethods well known in the art, to afford compounds of formula (II)wherein R₆ is as defined above. Compounds of formula (II) are thenN-protected to afford compounds of formula (IIe) wherein R₈ is anN-protecting group as described above. This is typically performed usingstandard protecting group chemistry following the procedures asdescribed in the literature referenced below.

As the next step, the compound (IIe) is converted to compound (IIf)according to methods illustrated herein in the Examples, or usingmethods well known in the art. Accordingly, generation of the anion atposition 4 of the pyroglutamic acid ester ring by treatment of IIe witha strong base, e.g. a strong lithium base followed by quenching withacetone in the presence of a Lewis acid provides an intermediatetertiary alcohol. The alcohol group is then converted into a leavinggroup by reaction with an appropriate electrophile. Elimination thenprovides the desired compound IIf, wherein R₃, R₆ and R₈ are as definedabove. Reference is made to the method described by Hanessian S. et al,J. Org. Chem. 2002, 67, 4261.

Then, the compound (IIf) is converted to compound (IIg) wherein R₃ andR₈ are as defined above by reducing the ester moiety to the alcoholaccording to methods illustrated herein in the Examples, or usingmethods well known in the art, typically by using a hydride such aslithium borohydride.

Compounds of formula (IIg) are then O-protected to afford compounds offormula (IV) wherein R₇ is an O-protecting group as described above andR₃ and R₈ are as defined above, according to methods illustrated hereinin the Examples, or using methods well known in the art. This istypically performed using standard protecting group chemistry followingthe procedures as described in the literature referenced below.

Once compounds of formula (IV) are prepared, preferably by one of theabove routes, they are further converted to compounds of formula (V).Reaction with an organometallic compound of formula (XIIc) wherein R₁and R₂ have meanings as defined for formula (A); and Y is, e.g. lithium;or (XIIc) represents a Grignard reagent; then affords compounds offormula (V) wherein R₁, R₂, R₃, R₇ and R₈ have meanings as definedherein above, also key intermediates for the preparation of compounds offormula (A) This is typically performed as illustrated herein in theExamples, or using methods well known in the art, Reference is made tothe method described by Houben-Weyl: Volume 4/1c, page 379-386,Reduktion I. Reduction of the benzylic carbonyl group using conventionalmethods, e.g. those described in “Organikum, organisch-chemischesGrundpraktikum”, 20th revised edition, VEB Deutscher Verlag derWissenschaften, Berlin 1999, followed by selective removal of theO-protecting group affords compounds of formula (VI) wherein R₁, R₂, R₃and R₈ have meanings as defined herein above. This is typicallyperformed as illustrated herein in the Examples, or using methods wellknown in the art, see e.g. Th. W. Greene & P. G. M. Wuts, “Protectivegroups in Organic Synthesis”, 2^(nd) Ed. (1991). See alsoRaney-Nickel-benzylic deoxygenation: Applied Catalysis A: General 219,page 281-289 (2001).

Compounds of formula (VI) may then be oxidized to carboxylic acids offormula (VII) wherein R₁, R₂, R₃ and R₈ have meanings as defined hereinabove, according to methods illustrated herein in the Examples, or usingmethods well known in the art, e.g., by treatment with sodiumhypochlorite and TEMPO in the presence of a phase transfer catalyst suchas Bu₄NBr. Reference is made to the methods described by a) F. Montanariet al., J.O.C., 54, 2970 (1989) and b) Review: H. van Bekkum et al.,Synthesis 1153 (1996).

Carboxylic acids of formula (VII) may first be converted to theiractivated derivatives of formula (VIIIa) wherein R₁, R₂, R₃ and R₈ havemeanings as defined herein above; and X represent e.g. halogen such asfluorine or chlorine; R₁₀OC(O)O— in which R₁₀ is C₁₋₂₀alkyl,C₃₋₁₂cycloalkyl, C₃₋₁₂cycloalkyl-C₁₋₆alkyl, C₆₋₁₀aryl orC₆₋₁₀aryl-C₁₋₆alkyl; Me(MeO)N—; or imidazolyl, also key intermediatesfor the preparation of compounds of formula (A). This is typicallyperformed as illustrated herein in the Examples, or using methods wellknown in the art, see e.g. for A) acid chlorides, see references a) R.W. Saalfrank et al., Angew. Chem., 102, 292 (1990) & H. Boehme et al.,Chem. Ber. 99, 879 (1966) b) Chem. Pharm. Bull., 13, 1472 (1965) &Synth. Commun., 30, 3439 (2000) & Bull. Korean Chem. Soc., Vol. 24, 895(2003); B) acid fluorides, see reference Tetrahedron Lett., 32, (10)1303 (1991) C) via imidazolide: see references R. V. Hoffman et al.,J.O.C., 62, 2292 (1997) or R. V. Hoffman et al., J.O.C., 62, 6240 (1997)or R. V. Hoffman et al., J.O.C., 67, 1045 (2002), or R. V. Hoffman etal., Tetrahedron, 53, 7119 (1997); or see J. Maibaum & D. Rich, J.O.C.,53, 869 (1988).

Subsequent coupling with a chiral malonate derivative of formula (VIIIb)wherein R₄ is as defined for formula (A); and R₉ is C₁₋₂₀alkyl,C₃₋₁₂cycloalkyl, C₃₋₁₂cycloalkyl-C₁₋₆alkyl, C₆₋₁₀aryl, C₂₋₂₀alkenyl orC₆₋₁₀aryl-C₁₋₆alkyl, preferably C₁₋₆alkyl or C₆₋₁₀aryl-C₁₋₄alkyl, morepreferably C₁₋₄ alkyl or benzyl, most preferably methyl, ethyl, t-butylor benzyl; then affords compounds of formula (IX) wherein R₁, R₂, R₃,R₄, R₈ and R₉ have meanings as defined herein above. This is typicallyperformed as illustrated herein in the Examples, or using methods wellknown in the art, see e.g. Journ. Med. Chem., 41, 2461 (1998).

Ester cleavage and decarboxylation of compound (IX) is conducted toafford compound of formula (X) wherein R₁, R₂, R₃, R₄, R₈ and R₉ havemeanings as defined herein above, also key intermediates for thepreparation of compounds of formula (A). The ester cleavage is typicallya hydrolysis or a hydrogenation, in case of a benzylic ester, accordingto methods well known in the art. The decarboxylation is typicallyperformed as illustrated herein in the Examples, or using methods wellknown in the art, see e.g. J. Med. Chem., 41, 2461 (1998). The ester,i.e. the compound of formula (X) wherein R′ is R₉, can be used as it isfor the next step or it can be hydrolysed to the respective acid whereR′ is H, if desired, prior to the next step. Hydrolysis can be effectedaccording to methods well known in the art.

As the next step the compound of formula (X) is subjected tostereoselective reduction of the C-4 carbonyl group and cyclization upontreatment with acid, which then affords compounds of formula (XI)wherein R₁, R₂, R₃, R₄ and R₈ have meanings as defined herein above. Thestereoselective reduction is typically performed as illustrated hereinin the Examples, or using methods well known in the art, Reference ismade to e.g. R. V. Hoffman et al. JOC, 67, 1045 (2002) and literaturereferences cited therein and R. V. Hoffman et al., JOC, 62, 2292 (1997),and T. Ikariya et al., J.O.C., 69, 7391 (2004) and literature referencescited therein.

The chiral malonate derivative of formula (VIIIb) wherein R⁴ and R⁹ areas defined herein which is used in the conversion of compound (VIIIa) asdiscussed above is an important synthesis building block for thepreparation of renin inhibitors. The chiral malonate derivative offormula (VIIIb) is available from a number of sources, eg. D-valine whenR⁴ is isopropyl as shown in Scheme 3 below. In this case R⁹ ispreferably methyl or ethyl. This route is applicable to any branchedC₃₋₆alkyl for R⁴.

D-valine is converted into D-2-hydroxy isovaleric acid via diazotizationusing Na nitrite in aqueous sulphuric acid. Alternatively, D-2-hydroxyisovaleric acid can be purchased commercially e.g. from Fluka orAldrich. According to literature procedures (Tetrahedron, 46, 6623(1990), J. Chem. Soc.; Perk. Trans. 1, (12), 1427 (1996), J. Org. Chem.,52, 4978 (1987)) the acid is esterified using e.g. potassium carbonateand R₉—X, e.g. MeI. As a next step the hydroxyl group of the D-2-hydroxyisovaleric acid ester is esterified with 4-nitrobenzene sulfonylchloride. This reaction is preferably conducted in the presence oftriethylamine and a catalytic amount of DMAP(dimethylaminopyridine)obtaining the R-enantiomer. The sulfonic acid ester or nosylate is thenalkylated with a suitable diester, e.g. malonic acid ester underconversion of the stereochemistry to yield the final triester.

Alternatively to the above schemes, compounds of formula (XI) can beobtained via an a route starting from compounds of formula (VI) or(VII), whereby compounds of formula (VI) or (VII) have been obtained byany of the conversions described e.g. in Schemes 1, 1a, 1b, 1c or 2alone or in combination. This route is outlined in Scheme 4 below. Inthis Scheme R₄ has been shown exemplary as i-propyl in order to bettervisualize the conversions. However, Scheme 4 is not limited to R₄ beingi-propyl but the compounds shown can be any branched C₃₋₆alkyl as setforth herein. Moreover, although Scheme 4 only illustrates the routeusing the alcohol (VI) to obtain in the next step the respectivealdehyde (XIV), in this alternative route one may also employ the acid(VII) and prepare the respective aldehyde (XIV) via esterification ofthe acid and subsequent reduction of the ester using DIBAL-H to yieldthe aldehyde (XIV).

The steps as outlined in Scheme 4 will be described in detail below aswell as in the Examples.

Step A0: The N-Boc-protected alcohol (VI) is selectively oxidized to thecorresponding aldehyde (XIV) wherein R₁, R₂, R₃, and R₈ have meanings asdefined herein. Typically this is performed by treatment with bleach andcatalytic amounts of Tempo. Preferably, the reaction is conducted underextensive stirring preferably in a biphasic solvent system likewater-toluene or water-toluene/EtOAc. Reference is made e.g. to a) F.Montanari et al., J.O.C., 54, 2970 (1989) and b) Review: H. van Bekkumet al., Synthesis 1153 (1996).

Step A: A suitable nucleophile, e.g. a propiolester-Li-salt, is added tothe Boc-protected aldehyde (XIV) to yield the acetylenic amino alcoholof formula (XV) wherein R₁, R₂, R₃, R₈ and R₉ have meanings as definedherein. The reaction is typically performed in THF at −78° C. Theresulting acetylenic amino alcohol (XV) is typically obtained as amixture of diastereomers (S,S) and (S,R). The acetylenic amino alcohol(XV) can be used without separation as the 2 epimers.

Step B: The triple bond of the acetylenic amino alcohol (XV) ishydrogenated to give the saturated γ-hydroxy ester (XVI) wherein R₁, R₂,R₃, R₈ and R₉ have meanings as defined herein. This conversion istypically performed in a mixture of toluene and acetic acid overplatinum oxide. The saturated γ-hydroxy ester (XVI) can be used withoutfurther purification.

Step C: The saturated y-hydroxy ester (XVI) is subjected tolactonization to obtain the γ-lactone of formula (XVII) wherein R₁, R₂,R₃, and R₈ have meanings as defined herein. Preferably, this step isperformed by treatment with acid, eg. AcOH, preferably in a solvent atelevated temperatures of 50 to 150° C., e.g. in hot toluene for 2 hoursat 95-100° C.

Step D: The γ-lactone of formula (XVII) is deprotected on the nitrogento yield the amino lactone of formula (XVIII) wherein R₁, R₂ and R₃ havemeanings as defined herein. This step is preferably performed bytreatment with an anhydrous acid, e.g. hydrogen chloride gas in ethylacetate preferably at room temperature to get the unprotectedδ-amino-γ-lactone as e.g. the hydrochloride.

Step E: The amino lactone of formula (XVIII) is converted into thecorresponding piperidinone of formula (XIX)) wherein R₁, R₂ and R₃ havemeanings as defined herein. This step is preferably performed bytreatment in a solvent such as methanol at e.g. room temperature fore.g. 24 hours in the presence of a base. The base can be an amine base,e.g. triethylamine and is preferably used in excess to give thecorresponding piperidone.

Step F: The hydroxyl and the amine moieties of the piperidinone offormula (XIX) are protected with a suitable protecting group byprocedures well known in the art to give the bis-protected piperidinoneof formula (XX) wherein R₁, R₂, R₃, R₇ and R₈ have meanings as definedherein. Preferably the piperidone from step E is treated in a solventsuch as THF with a suitable base, e.g. an amine base such astriethylamine, and a catalyst, e.g. N,N-dimethyl-aminopyridine and acarbonate, e.g. di-tert. butyldicarbonate preferably at room temperatureto give e.g. the bis-Boc-derivative.

Step G: A branched alkyl with a tertiary hydroxyl moiety is introducedon the piperidinone ring of the bis-protected piperidinone of formula(XX) to form the hydroxyl alkyl substituted piperidinone derivative offormula (XXI) wherein R₁, R₂, R₃, R₇ and R₈ have meanings as definedherein. Typically the bis-Boc-derivative is treated with a strong basesuch as LiHMDS to deliver the enolate, e.g. the Li-enolate. Thisreaction is performed in a suitable solvent, e.g, in THF, preferably attemperatures below 0° C., preferably −78° C. The enolate can then betreated preferably at that temperature with BF₃-diethyletherate followedby a suitable ketone, e.g. acetone, to give the adduct as a crystallineresidue after work up and crystallization from hexane.

Step H: The hydroxyl alkyl substituted piperidinone derivative offormula (XXI) is converted into the piperidinone derivative with anexocyclic double bond of formula (XXII) wherein R₁, R₂, R₃, R₇ and R₈have meanings as defined herein. Preferably, the teriary alcohol istreated in a solvent, e.g. dichloromethane, with a base, e.g. an aminebase such as triethylamine, as well as methanesulphonyl chloride to givea mixture of e.g. “iso propylidene” and “propenyliden” product (XXII)depending on the nature of R₄. The reaction is carried out by preferably−10 to 15° C., more preferably −5° C.

Step I: Double bond isomerisation of the exocyclic double bond of thepiperidinone derivative of formula (XXII) yields the olefin of formula(XXIII) wherein R₁, R₂, R₃, R₇ and R₈ have meanings as defined herein.Preferably, a solution of the propenyliden compound (XXII) or the likedepending on the nature of R₄, or a mixture of both compounds asobtained in step H is treated with a base (e.g. NEt₃ or DBU) in ethylacetate at room temperature to perform the double bond isomerisation tothe desired isopropylidene compound.

Step J: The olefin of formula (XXIII) is hydrogenated to obtain thealkyl substituted piperidinone derivative of formula (XXIV) wherein R₁,R₂, R₃, R₇ and R₈ have meanings as defined herein. Preferably, theolefin of formula (XXIII) is hydrogenated in a suitable solvent e.g.ethyl acetate, in the presence of small amounts of a base, e.g. an aminebase such as triethylamine, over Pt—C. This reaction is preferablyconducted at elevated temperatures and pressure or until the conversionis complete. Temperatures of 30-70° C., e.g. at 50° C. are preferred. Apressure of 2-10 bar, e.g. 5 bar, is preferred.

Step K: Ring opening of the piperidinone derivative of formula (XXIV)gives a γ-hydroxy acid intermediate which is subjected to lactonisationto provide compound of formula (XI) wherein R₁, R₂, R₃ and R₈ havemeanings as defined herein. Preferably, the compound from thehydrogenation step above is treated first with a base, e.g. an inorganicbase such as NaOH to yield the γ-hydroxy acid intermediate. Morepreferably, an aqueous solution, e.g. 2N, of sodium hydroxide is used. Asuitable cosolvent such as THF may be present. Preferably, a phasetransfer catalyst (e.g. TEBA-Cl) may also be present. The reaction ispreferably conducted at 20-60° C., more preferably at 40° C. Theobtained y-hydroxy acid, e.g. in the form of he sodium salt, is thentreated with acid, e.g. glacial acetic acid, to perform thelactonisation. The acid is typically used in excess.

Finally, compounds of formula (XI) may be converted to compounds offormula (A) wherein R₁, R₂, R₃, R₄ and R₅ are as defined herein above,by carrying out the remaining steps using reaction conditions asdescribed herein in the Examples, or according to methods well known inthe art, see e.g. EP-A-0678 503. Specifically, treatment with an amineH₂NR₅ wherein R₅ is as defined herein above leads to lactone ringopening of the compound of formula (XI) by to afford the amide offormula (XIII). This is typically performed as illustrated herein in theExamples, or using methods well known in the art, see e.g. EP-A-0678503. Finally, compounds of formula (XIII) may be converted to compoundsof formula (A) wherein R₁, R₂, R₃, R₄ and R₅ are as defined hereinabove, by removal of the N-protecting group of the compound of formula(XIII) to reveal the free amine, using standard protecting groupchemistry following the procedures as described in the literaturereferenced below, and optionally salt formation to obtain the compoundof formula (A) using reaction conditions as described herein in theExamples. Typical salt formation procedures are e.g. described in U.S.Pat. No. 5,559,111. These final steps are illustrated in Scheme 5.

Alternatively, compounds of formula (X) can be prepared by the followingsteps. The carboxylic acid group of the compound of formula (X) isreacted with an amine H₂NR₅ wherein R₅ is as defined herein above, usingpeptide coupling to afford the amide of formula (XII) according to wellknown literature and textbook procedures, see e.g. Houben-Weyl, Methodender Organische Chemie, 4^(th) Ed, Synthese von Peptiden 1.

Subsequent stereoselective reduction of the C4-carbonyl group of thecompound of formula (XII) affords the compound of formula (XIII).Reference is made e.g. to R. V. Hoffman et al. JOC, 67, 1045 (2002) andlit. cited therein & R. V. Hoffman et al., JOC, 62, 2292 (1997), M. T.Reetz et al, Chem. Commun. (1989), 1474. Finally, compounds of formula(XIII) may be converted to compounds of formula (A) wherein R₁, R₂, R₃,R₄ and R₅ are as defined herein above, by removal of the N-protectinggroup of compound (XIII) to reveal the free amine, using standardprotecting group chemistry following the procedures as described in theliterature referenced below, and optionally salt formation to obtain thecompound of formula (A) using reaction conditions as described herein inthe Examples Typical salt formation procedures are e.g. described inU.S. Pat. No. 5,559,111.

Other objects, features, advantages and aspects of the present inventionwill become apparent to those skilled in the art from the followingdescription, appended Examples and claims. It should be understood,however, that the description, appended claims, while indicatingpreferred embodiments of the invention, are given by way of illustrationonly. Various changes and modifications within the spirit and scope ofthe disclosed invention will become readily apparent to those skilled inthe art from reading the following.

Listed below are definitions of various terms used to describe thecompounds of the instant invention. These definitions apply to the termsas they are used throughout the specification unless they are otherwiselimited in specific instances either individually or as part of a largergroup. Any definition for one substituent can be combined with any otherdefinition for another substituent, including in both instancespreferred definitions.

R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl. Preferred embodiments are described below.

R₂ is halogen, C₁₋₄alkyl or C₁₋₄alkoxy. Preferred embodiments aredescribed below.

R₃ and R₄ are independently branched C₃₋₆alkyl. Preferred embodimentsare described below.

R₅ is cycloalkyl, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy-C₁₋₆alkyl,C₁₋₆alkanoyloxy-C₁₋₆alkyl, C₁₋₆aminoalkyl, C₁₋₆alkylamino-C₁₋₆alkyl,C₁₋₆dialkylamino-C₁₋₆alkyl, C₁₋₆alkanoylamino-C₁₋₆alkyl,HO(O)C—C₁₋₆alkyl, C₁₋₆alkyl-O—(O)C—C₁₋₆alkyl, H₂N—C(O)—C₁₋₆alkyl,C₁₋₆alkyl-HN—C(O)—C₁₋₆alkyl or (C₁₋₆alkyl)₂N—C(O)—C₁₋₆alkyl. Preferredembodiments are described below.

R₆ is C₁₋₂₀alkyl, C₃₋₁₂cycloalkyl, C₃₋₁₂cycloalkyl-C₁₋₆alkyl, C₆₋₁₀arylor C₆₋₁₀aryl-C₁₋₆alkyl. Preferred embodiments are described below.

R₇ is a suitable O-protecting group as known in the art. Examplesinclude C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy, C₆₋₁₀aryl-C₁₋₆alkyl,C₁₋₆alkoxy-carbonyl, C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl or (C₁₋₈alkyl)₃silyl.Preferred embodiments are described below.

R₈ is a suitable N-protecting group as known in the art. An N-protectinggroup is, for example, an amino protecting group which is conventionallyused in peptide chemistry (cf.: “Protective groups in OrganicSynthesis”, 5^(th). Ed. T. W. Greene & P. G. M. Wuts), especially inchemistry of protecting pyrrolidines.

Preferred protecting groups comprise, for example, (i) C₁-C₂-alkyl thatis mono-, di- or trisubstituted by phenyl, such as benzyl, (or)benzhydryl or trityl, wherein the phenyl ring is unsubstituted orsubstituted by one or more, e.g. two or three, residues e.g. thoseselected from the group consisting of C₁-C₇-alkyl, hydroxy,C₁-C₇-alkoxy, C₂-C₈-alkanoyl-oxy, halogen, nitro, cyano, and CF₃;phenyl-C1-C2-alkoxycarbonyl; and allyl or cinnamyl. Especially preferredare benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbony (Fmoc),benzyloxymethyl (BOM), pivaloyl-oxy-methyl (POM),trichloroethxoycarbonyl (Troc), 1-adamantyloxycarbonxyl (Adoc), but canalso be benzyl, cumyl, benzhydryl, trityl, allyl, alloc(allyloxycarbonyl). The protecting group can also be silyl, liketrialklysilyl, especially trimethylsilyl, tert.-butyl-dimethylsilyl,triethylsilyl, triisopropylsilyl, trimethylsilyethoxymethyl (SEM), andcan also be substituted sulfonyl or substituted sulfenyl.

Examples for R₈ include C₆₋₁₀aryl-C₁₋₆alkyl, and C₁₋₆alkyl-carbonyl,C₆₋₁₀aryl-carbonyl, C₁₋₆alkoxy-carbonyl, andC₆₋₁₀aryl-C₁₋₆alkoxycarbonyl. Further preferred embodiments aredescribed below.

R₉ is C₁₋₂₀alkyl, C₃₋₁₂cycloalkyl, C₃₋₁₂cycloalkyl-C₁₋₆alkyl, C₆₋₁₀aryl,C₂₋₂₀alkenyl or C₆₋₁₀aryl-C₁₋₆alkyl. In one embodiment R₉ is C₁₋₂₀alkyl,C₃₋₁₂cycloalkyl, C₃₋₁₂cycloalkyl-C₁₋₆alkyl, C₆₋₁₀aryl orC₆₋₁₀aryl-C₁₋₆alkyl. Preferred embodiments are described below.

As an alkyl, R₁ and R₂ may be linear or branched and preferably comprise1 to 6 C atoms, especially 1 or 4 C atoms. Examples are methyl, ethyl,n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl.

As a halogenalkyl, R₁ may be linear or branched and preferably comprise1 to 4 C atoms, especially 1 or 2 C atoms. Examples are fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.

As an alkoxy, R₁ and R₂ may be linear or branched and preferablycomprise 1 to 4 C atoms. Examples are methoxy, ethoxy, n- andi-propyloxy, n-, i- and t-butyloxy, pentyloxy and hexyloxy.

As an alkoxyalkyl, R₁ may be linear or branched. The alkoxy grouppreferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkylgroup preferably comprises 1 to 4 C atoms. Examples are methoxymethyl,2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl,6-methoxyhexyl, ethoxymethyl, 2ethoxyethyl, 3-ethoxypropyl,4-ethoxybutyl, 5-ethoxypentyl, 6-ethoxyhexyl, propyloxymethyl,butyloxymethyl, 2-propyloxyethyl and 2-butyloxyethyl.

As a C₁₋₆alkoxy-C₁₋₆alkyloxy, R₁ and R₇ may be linear or branched. Thealkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms,and the alkyloxy group preferably comprises 1 to 4 C atoms. Examples aremethoxymethyloxy, 2-methoxyethyloxy, 3-methoxypropyloxy,4-methoxybutyloxy, 5-methoxypentyloxy, 6-methoxyhexyloxy,ethoxymethyloxy, 2-ethoxyethyloxy, 3-ethoxypropyloxy, 4-ethoxybutyloxy,5-ethoxypentyloxy, 6-ethoxyhexyloxy, propyloxymethyloxy,butyloxymethyloxy, 2-propyloxyethyloxy and 2-butyloxyethyloxy.

As a branched alkyl, R₃ and R₄ preferably comprise 3 to 6 C atoms.Examples are i-propyl, and t-butyl, and branched isomers of pentyl andhexyl.

As a cycloalkyl, R₅ may preferably comprise 3 to 8 ring-carbon atoms, 3or 5 being especially preferred. Some examples are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. The cycloalkyl mayoptionally be substituted by one or more substituents, such as alkyl,halo, oxo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thiol,alkylthio, nitro, cyano, heterocyclyl and the like.

As an alkyl, R₅ may be linear or branched in the form of alkyl andpreferably comprise 1 to 6 C atoms. Examples of alkyl are listed hereinabove. Methyl, ethyl, n- and i-propyl, n-, and t-butyl are preferred.

As a C₁₋₆hydroxyalkyl, R₅ may be linear or branched and preferablycomprise 2 to 6 C atoms. Some examples are 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 2-, 3- or 4-hydroxybutyl,hydroxypentyl and hydroxyhexyl.

As a C₁₋₆alkoxy-C₁₋₆alkyl, R₅ may be linear or branched. The alkoxygroup preferably comprises 1 to 4 C atoms and the alkyl group preferably2 to 4 C atoms. Some examples are 2-methoxyethyl, 2-methoxypropyl,3-methoxypropyl, 2-, 3- or 4-methoxybutyl, 2-ethoxyethyl,2-ethoxypropyl, 3-ethoxypropyl, and 2-, 3- or 4-ethoxybutyl.

As a C₁₋₆alkanoyloxy-C₁₋₆alkyl, R₅ may be linear or branched. Thealkanoyloxy group preferably comprises 1 to 4 C atoms and the alkylgroup preferably 2 to 4 C atoms. Some examples are formyloxymethyl,formyloxyethyl, acetyloxyethyl, propionyloxyethyl and butyroyloxyethyl.

As a C₁₋₆aminoalkyl, R₅ may be linear or branched and preferablycomprise 2 to 4 C atoms. Some examples are 2-aminoethyl, 2- or3-aminopropyl and 2-, 3- or 4-aminobutyl.

As C₁₋₆alkylamino-C₁₋₆alkyl and C₁₋₆dialkylamino-C₁₋₆alkyl, R₅ may belinear or branched. The alkylamino group preferably comprises C₁₋₄alkylgroups and the alkyl group has preferably 2 to 4 C atoms. Some examplesare 2-methylaminoethyl, 2-dimethylaminoethyl, 2-ethylaminoethyl,2-ethylaminoethyl, 3-methylaminopropyl, 3-dimethylaminopropyl,4-methylaminobutyl and 4-dimethylaminobutyl.

As a HO(O)C—C₁₋₆alkyl, R₅ may be linear or branched and the alkyl grouppreferably comprises 2 to 4 C atoms. Some examples are carboxymethyl,carboxyethyl, carboxypropyl and carboxybutyl.

As a C₁₋₆alkyl-O—(O)C—C₁₋₆alkyl, R₅ may be linear or branched, and thealkyl groups preferably comprise independently of one another 1 to 4 Catoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonylethyl,3-methoxycarbonylpropyl, 4-methoxycarbonylbutyl, ethoxycarbonylmethyl,2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, and4-ethoxycarbonylbutyl.

As a H₂N—C(O)—C₁₋₆alkyl, R₅ may be linear or branched, and the alkylgroup preferably comprises 2 to 6 C atoms. Some examples arecarbamidomethyl, 2-carbamidoethyl, 2-carbamido-2,2-dimethylethyl, 2- or3-carbamidopropyl, 2-, 3- or 4-carbamidobutyl,3-carbamido-2-methylpropyl, 3-carbamido-1,2-dimethylpropyl,3-carbamido-3-ethylpropyl, 3-carbamido-2,2-dimethylpropyl, 2-, 3-, 4- or5-carbamidopentyl, 4-carbamido-3,3- or -2,2-dimethyibutyl.

As a C₁₋₆alkyl-HN—C(O)—C₁₋₆alkyl or (C₁₋₆alkyl)₂N—C(O)—C₁₋₆alkyl, R₅ maybe linear or branched, and the NH-alkyl group preferably comprises 1 to4 C atoms and the alkyl group preferably 2 to 6 C atoms. Examples arethe carbamidoalkyl groups defined herein above, whose N atom issubstituted, with one or two methyl, ethyl, propyl or butyl.

As an alkyl, R₆, R₇, R₉ and R₁₀ may be linear or branched and comprisepreferably 1 to 12 C atoms, 1 to 8 C atoms being especially preferred.Particularly preferred is a linear C₁₋₄alkyl. Some examples are methyl,ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl,nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octacyl andeicosyl. Especially preferred are methyl and ethyl.

As a cycloalkyl, R₆, R₉ and R₁₀ may preferably comprise 3 to 8ring-carbon atoms, 5 or 6 being especially preferred. Some examples arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl andcyclododecyl.

As a cycloalkyl-alkyl, R₆, R₉ and R₁₀ may comprise preferably 4 to 8ring-carbon atoms, 5 or 6 being especially preferred, and preferably 1to 4 C atoms in the alkyl group, 1 or 2 C atoms being especiallypreferred. Some examples are cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl or cyclopentylethyl, and cyclohexylmethyl or2-cyclohexylethyl.

As an alkoxycarbonyl, R₇ and R₈ may comprise a linear or branched alkylgroup which preferably comprises 1 to 4 C atoms. Examples are methoxy,ethoxy, n- and i-propyloxy, n-, i- and t-butyloxy, pentyloxy andhexyloxy.

As an arylalkoxycarbonyl, R₇ and R₈ may comprise a linear or branchedalkyl group which preferably comprises 1 to 4 C atoms and an arylmoiety, preferably phenyl. An example includes benzyloxycarbonyl.

As an alkenyl, R₉ may be linear or branched alkyl containing a doublebond and comprising preferably 2 to 12 C atoms, 2 to 8 C atoms beingespecially preferred. Particularly preferred is a linear C₂₋₄alkenyl.Some examples of alkyl groups are ethyl and the isomers of propyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,tetradecyl, hexadecyl, octacyl and eicosyl, each of which containing adouble bond. Especially preferred is allyl.

As an aryl, R₆, R₉ and R₁₀ are preferably phenyl or naphthyl.

As an aralkyl, R₆, R₇, R₈, R₉ and R₁₀ are preferably benzyl orphenethyl.

In a preferred embodiment, R₁ is C₁₋₆alkoxy-C₁₋₆alkyloxy as definedabove, more preferably methoxy- or ethoxy-C₁₋₄alkyloxy.

In a preferred embodiment, R₂ is alkoxy as defined above, morepreferably methoxy or ethoxy.

In a preferred embodiment, R₁ is methoxy- or ethoxy-C₁₋₄alkyloxy, and R₂is preferably methoxy or ethoxy. Particularly preferred are compounds offormula (A), wherein R₁ is 3-methoxypropyloxy and R₂ is methoxy.

In a preferred embodiment, R₃ and R₄ are in each case i-propyl.

In a preferred embodiment, R₅ is H₂N—C(O)—C₁₋₆alkyl,C₁₋₆alkyl-HN—C(O)—C₁₋₆alkyl or (C₁₋₆alkyl)₂N—C(O)—C₁₋₆alkyl, with thepreferred examples as described above, more preferably isH₂N—C(O)—C₁₋₆alkyl, most preferably carbamido-2,2-dimethylethyl.

In a preferred embodiment, R₆ is C₁₋₆alkyl, more preferably C₁₋₄alkyl,most preferably methyl or ethyl.

In a preferred embodiment, R₇ and R₈ are independentlyarylalkoxycarbonyl, alkoxycarbonyl, or aralkyl such as benzyl,t-butoxycarbonyl or benzyloxycarbonyl.

In a preferred embodiment, R₇ and R₈ are independently t-butoxy- orbenzyloxycarbonyl.

In a preferred embodiment, R₉ is C₁₋₆alkyl or C₆₋₁₀aryl-C₁₋₄alkyl, morepreferably C₁₋₄ alkyl or benzyl, most preferably methyl, ethyl, t-butylor benzyl.

Accordingly, preferred are the methods of the present invention, whereina compound of formula (A) has the formula

wherein R₁ is 3-methoxypropyloxy; R₂ is methoxy; and R₃ and R₄ areisopropyl; or a pharmaceutically acceptable salt thereof.

Further preferred are the methods of the present invention, wherein acompound of formula (B) is(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate, also known asaliskiren.

The present invention also relates to the following key intermediatesuseful when preparing the compound of formula (A). Each of these keyintermediates is an important synthetic building block for the synthesisof the compound of formula (A) both with respect to the functionalityand the stereochemistry. Each of these key intermediates can be preparedby the steps as outlined in the respective schemes 1, 1a, 1b, 1c, 2 and4 either taken alone or in an appropriate combination and by eitherfollowing the respective complete route as outlined in the schemes.Alternatively, these key intermediates can be prepared by starting fromany intermediate product obtainable at any of the stages as outlined inthe schemes, including the preceding intermediate product and, thus,performing only one conversion to the respective key intermediate.

Compounds of the formula

wherein R₃ is branched C₃₋₆alkyl, preferably i-propyl, and R₆ isC₁₋₂₀alkyl, C₃₋₁₂cycloalkyl, C₃₋₁₂cycloalkyl-C₁₋₆alkyl, C₆₋₁₀aryl orC₆₋₁₀aryl-C₁₋₆alkyl, preferably C₁₋₄alkyl, most preferably methyl orethyl.

Compounds of the formula

wherein R₃ is branched C₃₋₆alkyl, preferably i-propyl.

Compounds of the formula

wherein R₃ is branched C₃₋₆alkyl, preferably i-propyl, and R₈ is anN-protecting group, e.g. C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl,C₆₋₁₀aryl-carbonyl, C₁₋₆alkoxy-carbonyl, orC₆₋₁₀aryl-C₁₋₆alkoxycarbonyl.

Compounds of the formula

wherein R₃ is branched C₃₋₆alkyl, preferably i-propyl.

Compounds of the formula

wherein R₃ is branched C₃₋₆alkyl, preferably i-propyl; R₇ is anO-protecting group, e.g. C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy,C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₀aryl-C₁₋₆alkoxycarbonylor (C₁₋₈alkyl)₃silyl; and R₈ is an N-protecting group, e.g.C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl, C₆₋₁₀aryl-carbonyl,C₁₋₆alkoxy-carbonyl, or C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl; R₂ is halogen, C₁₋₄alkyl or C₁₋₄alkoxy; R₃ isbranched C₃₋₆alkyl; R₇ is C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy,C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₀aryl-C₁₋₆alkoxycarbonylor (C₁₋₈alkyl)₃silyl; and R₈ is C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl,C₆₋₁₀aryl-carbonyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl;are useful intermediates for the preparation of compounds of formula(A).

Preferred are the compounds of formula (V) having the formula

wherein R₁ is 3-methoxypropyloxy; R₂ is methoxy; R₃ is isopropyl; andR₁₁ and R₁₂ are independently t-butyl or benzyl.

Preferred are the compounds of formula (V′) wherein R₁₁ and R₁₂ aret-butyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl; R₂ is halogen, C₁₋₄alkyl or C₁₋₄alkoxy; R₃ isbranched C₃₋₆alkyl; and R₈ is C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl,C₆₋₁₀aryl-carbonyl, C₁₋₆alkoxy-carbonyl, C₈₋₁₀aryl-C₁₋₆alkoxycarbonyl;are also useful intermediates for the preparation of compounds offormula (A).

Preferred are the compounds of formula (VII) having the formula

wherein R₁ is 3-methoxypropyloxy; R₂ is methoxy; R₃ is isopropyl; andR₁₂ is t-butyl or benzyl.

Preferred are the compounds of formula (VII′) wherein R₁₂ is t-butyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl; R₂ is halogen, C₁₋₄alkyl or C₁₋₄alkoxy; R₃ and R₄are independently branched C₃₋₆alkyl; R₈ is C₈₋₁₀aryl-C₁₋₆alkyl,C₁₋₆alkyl-carbonyl, C₆₋₁₀aryl-carbonyl, C₁₋₆alkoxy-carbonyl,C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl; and R₉ is C₁₋₂₀alkyl, C₃₋₁₂cycloalkyl,C₃₋₁₂cycloalkyl-C₁₋₆alkyl, C₆₋₁₀aryl, C₂₋₂₀alkenyl orC₈₋₁₀aryl-C₁₋₆alkyl, preferably C₁₋₆alkyl or C₆₋₁₀aryl-C₁₋₄alkyl,preferably C₁₋₄ alkyl or benzyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl; R₂ is halogen, C₁₋₄alkyl or C₁₋₄alkoxy; R₃ and R₄are independently branched C₃₋₈alkyl; and R₈ is C₆₋₁₀aryl-C₁₋₆alkyl,C₁₋₆alkyl-carbonyl, C₈₋₁₀aryl-carbonyl, C₁₋₆alkoxy-carbonyl,C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl; are also useful intermediates for thepreparation of compounds of formula (A).

Preferred are the compounds of formula (X) having the formula

wherein R₁ is 3-methoxypropyloxy; R₂ is methoxy; R₃ is isopropyl; R₄ isisopropyl; and R₁₂ is t-butyl or benzyl.

Preferred are the compounds of formula (X′) wherein R₁₂ is t-butyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl, preferably 3-methoxypropyloxy; R₂ is halogen,C₁₋₄alkyl or C₁₋₄alkoxy, preferably methoxy; R₃ and R₄ are independentlybranched C₃₋₆alkyl, preferably each isopropyl; and R₈ is an N-protectinggroup, e.g. C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl, C₆₋₁₀aryl-carbonyl,C₁₋₆alkoxy-carbonyl, or C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl, preferably 3-methoxypropyloxy; R₂ is halogen,C₁₋₄alkyl or C₁₋₄alkoxy, preferably methoxy; R₃ is branched C₃₋₆alkyl,preferably isopropyl; and R₈ is an N-protecting group, e.g.C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl, C₆₋₁₀aryl-carbonyl,C₁₋₆alkoxy-carbonyl, or C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl; R₉ is C₁₋₂₀alkyl,C₃₋₁₂cycloalkyl, C₃₋₁₂cycloalkyl-C₁₋₆alkyl, C₆₋₁₀aryl, C₂₋₂₀alkenyl orC₆₋₁₀aryl-C₁₋₆alkyl, preferably C₁₋₆alkyl or C₆₋₁₀aryl-C₁₋₄alkyl,preferably C₁₋₄ alkyl or benzyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl, preferably 3-methoxypropyloxy; R₂ is halogen,C₁₋₄alkyl or C₁₋₄alkoxy, preferably methoxy; R₃ is branched C₃₋₆alkyl,preferably isopropyl; and R₈ is an N-protecting group, e.g.C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl, C₆₋₁₀aryl-carbonyl,C₁₋₆alkoxy-carbonyl, or C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl; R₉ is C₁₋₂₀alkyl,C₃₋₁₂cycloalkyl, C₃₋₁₂cycloalkyl-C₁₋₆alkyl, C₆₋₁₀aryl, C₂₋₂₀alkenyl orC₆₋₁₀aryl-C₁₋₆alkyl, preferably C₁₋₆alkyl or C₆₋₁₀aryl-C₁₋₄alkyl,preferably C₁₋₄ alkyl or benzyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl, preferably 3-methoxypropyloxy; R₂ is halogen,C₁₋₄alkyl or C₁₋₄alkoxy, preferably methoxy; R₃ is branched C₃₋₆alkyl,preferably isopropyl; and R₈ is an N-protecting group, e.g.C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl, C₆₋₁₀aryl-carbonyl,C₁₋₆alkoxy-carbonyl, or C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl, preferably 3-methoxypropyloxy; R₂ is halogen,C₁₋₄alkyl or C₁₋₄alkoxy, preferably methoxy; R₃ is branched C₃₋₆alkyl,preferably isopropyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl, preferably 3-methoxypropyloxy; R₂ is halogen,C₁₋₄alkyl or C₁₋₄alkoxy, preferably methoxy; R₃ is branched C₃₋₆alkyl,preferably isopropyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl, preferably 3-methoxypropyloxy; R₂ is halogen,C₁₋₄alkyl or C₁₋₄alkoxy, preferably methoxy; R₃ is branched C₃₋₆alkyl,preferably isopropyl; R₇ is an O-protecting group, e.g. C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyloxy, C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkoxy-carbonyl,C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl or (C₁₋₈alkyl)₃silyl; and R₈ is anN-protecting group, e.g. C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl,C₆₋₁₀aryl-carbonyl, C₁₋₆alkoxy-carbonyl, orC₆₋₁₀aryl-C₁₋₆alkoxycarbonyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl, preferably 3-methoxypropyloxy; R₂ is halogen,C₁₋₄alkyl or C₁₋₄alkoxy, preferably methoxy; R₃ is branched C₃₋₆alkyl,preferably isopropyl; R₇ is an O-protecting group, e.g. C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyloxy, C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkoxy-carbonyl,C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl or (C₁₋₈alkyl)₃silyl; and R₈ is anN-protecting group, e.g. C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl,C₈₋₁₀aryl-carbonyl, C₁₋₆alkoxy-carbonyl, orC₆₋₁₀aryl-C₁₋₆alkoxycarbonyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl, preferably 3-methoxypropyloxy; R₂ is halogen,C₁₋₄alkyl or C₁₋₄alkoxy, preferably methoxy; R₃ is branched C₃₋₆alkyl,preferably isopropyl; R₇ is an O-protecting group, e.g. C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyloxy, C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkoxy-carbonyl,C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl or (C₁₋₈alkyl)₃silyl; and R₈ is anN-protecting group, e.g. C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl,C₆₋₁₀aryl-carbonyl, C₁₋₆alkoxy-carbonyl, orC₆₋₁₀aryl-C₁₋₆alkoxycarbonyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl, preferably 3-methoxypropyloxy; R₂ is halogen,C₁₋₄alkyl or C₁₋₄alkoxy, preferably methoxy; R₃ is branched C₃₋₆alkyl,preferably isopropyl; R₇ is an O-protecting group, e.g. C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyloxy, C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkoxy-carbonyl,C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl or (C₁₋₈alkyl)₃silyl; and R₈ is anN-protecting group, e.g. C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl,C₆₋₁₀aryl-carbonyl, C₁₋₆alkoxy-carbonyl, orC₆₋₁₀aryl-C₁₋₆alkoxycarbonyl.

Compounds of the formula

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl, preferably 3-methoxypropyloxy; R₂ is halogen,C₁₋₄alkyl or C₁₋₄alkoxy, preferably methoxy; R₃ is branched C₃₋₆alkyl,preferably isopropyl; R₇ is an O-protecting group, e.g. C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyloxy, C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkoxy-carbonyl,C₆₋₁₀aryl-C₁₋₆alkoxycarbonyl or (C₁₋₈alkyl)₃silyl; and R₈ is anN-protecting group, e.g. C₆₋₁₀aryl-C₁₋₆alkyl, C₁₋₆alkyl-carbonyl,C₆₋₁₀aryl-carbonyl, C₁₋₆alkoxy-carbonyl, orC₆₋₁₀aryl-C₁₋₆alkoxycarbonyl.

Moreover, the present invention is also directed to the chiral malonatederivative of formula (VIIIb) which is an important synthesis buildingblock for the preparation of renin inhibitors:

wherein R⁴ and R⁹ are as defined herein. Particularly preferred is thechiral malonate derivative of formula (VIII′b)

Preferably, the substituent R⁹ is methyl or ethyl, most preferablymethyl.

As indicated herein above, compounds of the present invention can beconverted into acid addition salts. The acid addition salts may beformed with mineral acids, organic carboxylic acids or organic sulfonicacids, e.g., hydrochloric acid, fumaric acid and methanesulfonic acid,respectively.

In view of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a compound is referred toin this context, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in the formof their hydrates, or include other solvents used for theircrystallization.

The present invention further includes any variant of the above process,in which an inter-mediate product obtainable at any stage thereof, e.g.a compound of formula (IIa), formula (IIb), formula (IIc), formula(IId), formula (IIe), formula (IIf), formula (IIg), formula (III),formula (IV), formula (V), formula (VI), formula (VII), formula (VIII),formula (IX) formula (X), formula (XI), formula (XII), formula (XIII),formula (XIV), formula (XV), formula (XVI), formula (XVII), formula(XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII),formula (XXIII) or formula (XXIV) is used as the starting material, andthe remaining steps are carried out, or in which the reaction componentsare used in the form of their salts. Moreover, any of the alternativeroutes may be combined appropriately via common intermediates to yieldthe compounds of formula (A).

When required, protecting groups may be introduced to protect thefunctional groups present from undesired reactions with reactioncomponents under the conditions used for carrying out a particularchemical transformation of the present invention. The need and choice ofprotecting groups for a particular reaction is known to those skilled inthe art and depends on the nature of the functional group to beprotected (amino, hydroxyl, thiol etc.), the structure and stability ofthe molecule of which the substituent is a part and the reactionconditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, for example, in McOmie,“Protective Groups in Organic Chemistry”, Plenum Press, London, N.Y.(1973); Greene and Wuts, “Protective Groups in Organic Synthesis”, JohnWiley and Sons, Inc., NY (1999).

In the processes cited herein, activated derivatives of carboxylic acidsof formula (VIIIa), include acid chlorides, bromides and fluorides,mixed anhydrides, lower alkyl esters and activated esters thereof. Mixedanhydrides are preferably such from pivalic acid, or lower alkylhemiesters of carbonic acids, such as ethyl or isobutyl analogs.Activated esters include, for example, succinimido, phthalimido or4-nitrophenyl esters. Carboxylic acids of formula (VII) can be convertedto their activated derivatives using methods described herein or in theart.

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluent, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures (preferably ator near the boiling point of the solvents used), and at atmospheric orsuper-atmospheric pressure.

Suitable solvents are water and organic solvents, especially polarorganic solvents, which can also be used as mixtures of at least twosolvents. Examples of solvents are hydrocarbons (petroleum ether,pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene,xylene), halogenated hydrocarbon (dichloromethane, chloroform,tetrachloroethane, chlorobenzene); ether (diethyl ether, dibutyl ether,tetrahydrofuran, dioxane, ethylene glycol dimethyl or diethyl ether);carbonic esters and lactones (methyl acetate, ethyl acetate, methylpropionate, valerolactone); N,N-substituted carboxamides and lactams(dimethylformamide, dimethylacetamide, N-methylpyrrolidone); ketones(acetone, methylisobutylketone, cyclohexanone); sulfoxides and sulfones(dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone); alcohols(methanol, ethanol, n- or i-propanol, n-, i- or t-butanol, pentanol,hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl or dihydroxymethylcyclohexane, benzyl alcohol, ethylene glycol, diethylene glycol,propanediol, butanediol, ethylene glycol monomethyl or monoethyl ether,and diethylene glycol monomethyl or monoethyl ether; nitriles(acetonitrile, propionitrile); tertiary amines (trimethylamine,triethylamine, tripropylamine and tributylamine, pyridine,N-methylpyrrolidine, N-methylpiperazine, N-methylmorpholine) and organicacids (acetic acid, formic acid).

The processes described herein above are preferably conducted underinert atmosphere, more preferably under nitrogen atmosphere.

Compounds of the present invention may be isolated using conventionalmethods known in the art, e.g., extraction, crystallization andfiltration, and combinations thereof.

The following Examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centrigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 5 and 50 mmHg(=20-133 mbar). The structure of final products, intermediates andstarting materials is confirmed by standard analytical methods, e.g.,microanalysis and spectroscopic characteristics, e.g., MS, IR and NMR.In general, abbreviations used are those conventional in the art.

EXAMPLE 1 Preparation of (S)-5-hydroxymethyl-pyrrolidin-2-one

A suspension of 275 g of lithium borohydride in 15 L of anhydroustetrahydrofuran is cooled to 10° C. and a solution of 1.6 kg of(S)-5-oxo-pyrrolidine-2-carboxylic acid methyl ester in 8 L oftetrahydrofuran is added within 2 hours. The resulting suspension iswarmed to 40° C. and stirred for a further 3 hours. Water (1.8 L) isthen added and the mixture filtered. The solid is then suspended in 7 Lof tetrahydrofuran and heated to reflux for 75 minutes. After this timethe mixture is cooled to 25° C. and filtered. The filtrate is treatedslowly with 500 mL of a 1.0 M solution of oxalic acid in water at roomtemperature. The resulting suspension is filtered and the solid washedwith 5 L of tetrahydrofuran. The solvent is then removed from thefiltrate to provide an oil. The oil is re-dissolved in a mixture of 6.3L of ethyl acetate and 0.7 L of ethanol at elevated temperature and theslightly cloudy solution filtered. The clear solution is cooled to −25°C. and the resulting suspension stirred for 2 hours. The solid iscollected by filtration, washed with ethyl acetate and dried to give thetitle compound.

The starting material may be prepared as follows.

A suspension of 0.4 kg of Dowex-H⁺ ion exchange resin in 30 L ofmethanol containing 2 kg of D-pyroglutamic acid is stirred at relfuxtemperature for 72 hours. The mixture is cooled to room temperature anda further 0.17 kg of Dowex-H resin and 30 L of methanol is added and themixture heated to reflux. Methanol is removed by distillation undervacuum. The reaction mixture is then treated with a further 30 L ofmethanol and the distillation repeated. This is repeated a furthertwice. Finally the mixture is concentrated in vacuum to a volume ofaround 10 L filtered and the solid washed with 10 L of methanol. Thefiltrate and washings are combined and the methanol removed bydistillation to give an oil. The pure methyl ester is isolated byfractional distillation at 120-132° C. and 0.70 mBar to give therequired ester.

EXAMPLE 2 Preparation of (3S,5S)-5-hydroxymethyl-3-isopropyl-pyrrolidone

A solution of 16.5 g of(3R,6S,7aS)-6-isopropyl-3-phenyltetrahydro-pyrrolo[1,2-c]oxazol-5-one in175 mL of dichloromethane is treated with 15.35 g of trifluoroaceticacid at room temperature. The resulting solution is stirred for 24 hoursat room temperature and a further 14 g of trifluoroacetic acid added.Stirring is continued for a further 24 hours and the solvent removed invacuum. The residue is treated with 50 mL of water and 100 mL ofdichloromethane and the pH of the two-phase mixture adjusted to 12 withconcentrated sodium hydroxide solution. Solid sodium chloride is addedand the mixture stirred. The organic layer is removed under reducedpressure to give (3S,5S)-5-hydroxymethyl-3-isopropyl-pyrrolidin-2-one asa semi-solid. mp. 55.9° C., [α]_(D)=+47.9° (1% in MeOH)

The starting material may be prepared as follows:

A suspension of 148.5 g of (S)-5-hydroxymethyl-pyrrolidin-2-one in 891mL of toluene is treated with 172.1 mL of benzaldehyde at roomtemperature. p-Toluenesulphonic acid (2.94 g) is added and the reactionmixture stirred at reflux for 20 hours with azeotropic removal of water.The reaction mixture is treated with 500 mL of a 5% solution of sodiumhydrogen carbonate in water. The organic layer is separated and washedonce with 500 mL of a 40% solution of sodium bisulphite solutionfollowed by 2×250 mL of water. The organic layer is dried with sodiumsulphate, filtered and the solvent removed to give an oil. Fractionaldistillation in vacuum produces pure(3R,7aS)-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazol-5-one.

A suspension of 450 g of a 60% dispersion of sodium hydride in mineraloil in 3.3 L of tetrahydrofuran is warmed to 50° C. and treated with 1.8kg of diethyl carbonate. A solution of 800 g(3R,7aS)-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazol-5-one in 1.6 L oftetrahydrofuran is added within 15 minutes and the resulting mixturestirred at 55° C. for 180 minutes. At 55-60° C. a solution of 1.85 kg ofisopropyl bromide in 1.8 kg of dimethyl formamide is added maintainingthe temperature between 55-60° C. Finally the reaction mixture waswarmed to reflux and stirred for 20 hours. The reaction mixture iscooled to room temperature and treated with 5 L of a 10% solution ofcitric acid in water. The reaction mixture is extracted twice with 3 Lof ethyl acetate and the organic extracts combined. The organic layersare washed twice with brine and dried. Removal of the solvent gave 1.84kg of an oil. The oil is chromatographed on silica-gel usinghexane/ethyl acetate mixtures. The product containing fractions arecombined and the solvent is removed to give the desired compound as anoil. Crystallisation from an ethyl acetate/hexane mixture delivers 730 gof(3R,6R,7aS)-6-isopropyl-5-oxo-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazole-6-carboxylicacid ethyl ester. A solution of 960 g of(3R,6R,7aS)-6-isopropyl-5-oxo-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazole-6-carboxylicacid ethyl ester in 8 L of tetrahydrofuran is treated with 3.33 L of a2.0 M solution of sodium hydroxide at room temperature. The reactionmixture is stirred for 24 hours toluene (5.15 L) is added and thereaction pH adjusted to between 2-4 with a 10% solution of citric acid.The layers are separated and the aqueous layer saturated with sodiumchloride. The aqueous layer is washed with 4 L of toluene and theorganic layers combined and dried. The toluene solution is heated toreflux for 48 hours. Finally the solution is cooled to 70° C. and thetoluene removed under a slight negative pressure to give(3R,6S,7aS)-6-isopropyl-3-phenyltetrahydro-pyrrolo[1,2-c]oxazol-5-one.

EXAMPLE 3 Preparation of(3S,5S)-5-tert-butoxycarbonyloxymethyl-3-isopropyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester

Route A:

A solution of 20.14 g of(3S,5S)-5-hydroxymethyl-3-isopropyl-pyrrolidin-2-one in 200 mL oftetrahydrofuran is treated with 39.36 g of di-tert-butyl dicarbonate,17.23 g of triethylamine and 1.04 g of dimethylamino pyridine. Themixture is stirred at room temperature for 24 hours and warmed to 40° C.for 6 hours. The solvent is removed under reduced pressure and theresidue treated with 60 mL of a 10% solution of citric acid and 200 mLof ethyl acetate. The organic layer is removed and the aqueous layerre-extracted with 200 mL of ethyl acetate. The combined organic layersare concentrated to a volume of around 40 mL and 50 mL of hexane isadded. The thin suspension is cooled to 0° C. and stirred overnight. Thecrystalline solid is collected by filtration, washed and dried to givethe title compound. X-ray single crystal! analysis of the compoundconfirms the absolute configuration on both stereo centers. mp.:111-112° C., [α]_(D)=−60.3° (1% CH₂Cl₂).

¹H-NMR: 4.27-4.22 (2H, brm), 4.11-4.15 (1H, dd), 2.59-2.65 (1H, m),2.16-2.21 (1H, brm), 1.88-1.93 (2H, brm), 1.50 (9H, s), 1.44 (9H, s),0.96 (3H, d), 0.82 (3H, d).

Route B:

A solution of 12.8 g(3S,5S)-5-hydroxymethyl-3-isopropyl-2-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester in 100 mL of dichloromethane is treated with 0.5 g ofdimethylamino pyridine is treated with 7.8 g di-tert-butyl dicarbonateat room temperature. The mixture is stirred for 4 hours at roomtemperature. The reaction mixture is then washed twice with 400 mL of0.5 M sulphuric acid. The organic phase is separated and the solventremoved to give the title compound as a semi-crystalline solid.

The starting material is prepared as follows:

A solution of 387 g of L-pyro-glutamic acid in 300 mL ofdimethylformamide is treated with 103.6 g of potassium carbonate at roomtemperature. Benzyl bromide (35.6 mL) is added and the suspensionstirred room temperature for 4 hours. The suspension is filtered and thesolid washed with 300 mL of acetone. The filtrate is evaporated at 50°C. to give an oil. The oil is dissolved in 300 mL of ethyl acetate andwashed with 300 mL of water. The aqueous phase is re-extracted with 150mL of ethyl acetate and the organic layers combined, dried and thesolvent removed to give (S)-5-oxo-pyrrolidine-2-carboxylic acid benzylester as an oil.

To a solution of 78.9 g of (S)-5-oxo-pyrrolidine-2-carboxylic acidbenzyl ester in 400 mL of dichloromethane is added 2.20 g ofdimethylaminopyridine and 78.54 g of di-tert-butyl carbonate at roomtemperature. The mixture is stirred for 4 hours at room temperature. Thereaction mixture is then washed twice with 400 mL of 0.5 M sulphuricacid. The organic phase is separated and the solvent removed to give(S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butylester as a semi-crystalline solid.

A solution of lithium hexamethyldisilazide in tetrahydrofuran is cooledto −78° C. and treated with a solution of 15.95 g of(S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butylester in 100 mL of tetrahydrofuran maintaining the temperature at −78°C. The resulting mixture was stirred for 40 minutes and a mixture of 40mL of acetone and 7 mL of boron trifluoride diethyl etherate addedwithin 20 minutes. The reaction mixture is stirred for 2.5 hours at −78°C. and 300 mL of a 10% solution of citric acid added and the reactionmixture warmed to room temperature. The layers are separated and theaqueous layer is re-extracted with 300 mL of dichloromethane. Thecombined organic layers are dried, filtered and the solvent removed togive (S)-4-(1-hydroxy-1-methyl-ethyl)-5-oxo-pyrrolidine-1,2-dicarboxylicacid 2-benzylester 1-tert-butyl ester as an oil.

A solution of 75.8 g of(S)-4-(1-hydroxy-1-methyl-ethyl)-5-oxo-pyrrolidine-1,2-dicarboxylic acid2-benzylester 1-tert-butyl ester in 200 mL of tetrahydrofuran is treatedwith 41.8 g of triethylamine and 1.2 g of dimethylamino pyridine andcooled to 0° C. Oxalic acid methyl ester chloride (31.7 mL) is addeddropwise within 60 minutes. The reaction mixture is stirred for 24 hoursat room temperature and 200 mL of tert-butyl methyl ether and 200 mL ofwater is added. The organic layer is separated and washed with 100 mL ofsaturated sodium bicarbonate solution followed by 100 mL of water. Theorganic phase is dried and the solvent removed to give 87.9 g of theintermediate oxalic acid ester as an oil. This oil is re-dissolved in350 mL of toluene and treated sequentially with 0.6 g ofazobisisobutyronitrile and 100.7 mL of tri-n-butyl tin hydride. Themixture is heated to reflux for 60 minutes and a further 0.6 g portionof azobisisobutyronitrile is added. This is continued for a total of 4hours (5 additions). The reaction mixture is concentrated in vacuum togive an oil. The oil is re-dissolved in 300 mL of acetonitrile andwashed 4 times with 400 mL of hexane. The acetonitrile phase isconcentrated in vacuum to give an oil. Chromatography on silica-gel withethyl acetate/hexane mixtures, combination of the product containingfractions and removal of the solvent gives(2S,4S)-4-isopropyl-5-oxo-pyrrolidine-1,2-dicarboxylic acid -2-benzylester-1-tert-butyl ester.

A suspension of 27 g of lithium borohydride in 15 mL of anhydroustetrahydrofuran is cooled to 10° C. and a solution of 15.4 g of(2S,4S)-4-isopropyl-5-oxo-pyrrolidine-1,2-dicarboxylic acid -2-benzylester-1-tert-butyl ester in 80 mL of tetrahydrofuran is added within 2hours. The resulting suspension is warmed to 40° C. and stirred for afurther 3 hours. Water (800 mL) is then added and the mixture filtered.The solid is then suspended in 700 mL of tetrahydrofuran and heated toreflux for 75 minutes. After this time the mixture is cooled to 25° C.and filtered. The filtrate is treated slowly with 500 mL of a 1.0 Msolution of oxalic acid in water at room temperature. The resultingsuspension is filtered and the solid washed with 500 mL oftetrahydrofuran. The solvent is then removed from the filtrate toprovide an oil. The oil is re-dissolved in a mixture of 630 mL of ethylacetate and 0.07 L of ethanol at elevated temperature and the slightlycloudy solution filtered. The clear solution is cooled to −25° C. andthe resulting suspension stirred for 2 hours. The solid is collected byfiltration, washed with ethyl acetate and dried to give(3S,5S)-5-hydroxymethyl-3-isopropyl-2-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester.

EXAMPLE 4 Preparation of Carbonic Acid(2S,4S)-2-tert-butylcarbonylamino-4-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-5-methyl-hexylestertert-butyl ester

A solution of 7.9 g of 4-bromo-1-methoxy-2-(3-methoxypropoxy)-benzene in125 mL of tetrahydrofuran is cooled to −78° C. A solution ofn-butyllithium (14.219 g of a 1.6 M solution in hexane) is added within50 minutes. The reaction mixture is stirred for 90 minutes at −78° C.and treated slowly with 75 mL of a tetrahydrofuran solution of 8.93 g of(3S,5S)-5-tert-butoxycarbonyloxymethyl-3-isopropyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester. The resulting reaction mixture is stirred for 3hours at −78° C. Finally the temperature is raised to −40° C. and themixture stirred for 45 minutes. Acetic acid (4 mL) was added and thesolvent removed by evaporation. The residue is dissolved in 100 mL ofethyl acetate and washed with two 75 mL portions of saturated sodiumbicarbonate solution followed by one portion of 150 mL of water. Theorganic phase was dried and the solvent removed to give an oil.Chromatography on silica-gel, eluting with hexane/ethyl acetate gives,after combination of the product containing fractions and removal of thesolvent, affords the title compound as an oil.

¹H-NMR (CDCl₃) 7.50(2H, m), 6.81(1H, m), 4.60(1H, d), 4.15(2H, t),4.05(2H, m), 3.90(3H, s), 3.55(2H, t), 3.40(1H, m), 3.35(3H, s),2.15(2H, m), 2.05(1H, m), 1.60(1H, m), 1.45(9H, s), 1.40-1.20(9H, Brs),1.00(3H, d), 0.90(3H, d).

EXAMPLE 5 Preparation of Carbonic Acid(2S,4S)-2-tert-butylcarbonylamino-4-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-5-methyl-hexylestertert-butyl ester

Carbonic acid(2S,4S)-2-tert-butylcarbonylamino-4-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-5-methyl-hexylestertert-butyl ester (2.67 g) is dissolved in 25 mL of a mixture ofethanol/acetic acid, 2/1 at room temperature. Palladium metal, 10% oncharcoal (0.3 g) is added and the suspension placed under an atmosphereof hydrogen at a pressure of 5 bar. Hydrogenation is continued for 3days at 50° C. with periodic addition of more catalyst. The reactionmixture is filtered and the solvent removed to give an oil. The oil ispurified by chromatography on silica-gel eluting with hexane/ethylacetate mixtures. The product fractions are combined and the solvent isremoved to give the title compound as an oil.

EXAMPLE 6 Preparation of((1S,3S)-1-hydroxymethyl-3-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-4-methylpentyl}-carbamicacid tert-butyl ester

Regioselective hydrolysis is carried out according to a literatureprocedure, e.g. as described in J. Amer. Chem. Soc., 2000, 122, 10708.

EXAMPLE 7 Preparation of(2S,4S)-2-tert-butoxycarbonylamino-4-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-5-methylhexanoicacid

To a solution of 4.39 g{(1S,3S)-1-hydroxymethyl-3-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-4-methylpentylycarbamicacid tert-butyl ester in 50 mL of dichloromethane is cooled to 0° C. andtreated with TEMPO (0.2 g), 25 mL of a 2.75 M solution of potassiumbromide and 15 mL of a 1.6 M solution of potassium hydrogen carbonatesolution. The rapidly stirred two-phase system is treated with bleach(15 mL of a 11% solution) and the mixture stirred for 60 minutes at 0°C. A 1.0 M solution of sodium thiosulphate is added and the mixturestirred for 15 minutes at room temperature. The organic layer is thenseparated and washed twice with 100 mL of water. The solvent is removedto provide the intermediate alcohol as an oil which is used directly forthe next step. The oil is dissolved in 20 mL of tert-butanol and 5 mL of2-methyl-2-butene is added. A solution of sodium chlorite (1.2 g, of a80% solution) and sodium dihydrogen phosphate (10.03 g) in 20 mL ofwater is added dropwise over 15 minutes. The reaction mixture is stirredfor 3 hours at room temperature. The mixture is then diluted with brineand extracted three times with 50 mL of dichloromethane. The combinedorganic layers are dried and the solvent is removed to give the titlecompound as an oil.

EXAMPLE 8 Preparation of(2S,5S,7S)-5-tert-butoxycarbonylamino-3-ethoxycarbonyl-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-8-methyl-4-oxo-3-propoxycarbonyl-nonanoicacid ethyl ester

A solution of 4.53 g of(2S,4S)-2-tert-butoxycarbonylamino-4-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-5-methylhexanoicacid in 25 mL of toluene is heated to reflux and oxalyl chloride (1.75g) is added. The mixture is then stirred at room temperature. Thesolvent is then removed in vacuum and a further 25 mL of toluene added.Distillation is repeated and a further 25 mL of toluene added.Distillation is repeated to give the acid chloride as an oil. This oilis re-dissolved in tetrahydrofuran and cooled to 0° C. and added to asolution of 11 mmol of the sodium salt of(R)-2-(bis-ethoxycarbonylmethyl)-3-methylbutyric acid ethyl ester intetrahydrofuran (prepared by treatment of(R)-2-(bis-ethoxycarbonyl-methyl)-3-methylbutyric acid ethyl ester withsodium hydride). The mixture is stirred for 2 hours at room temperatureand 20 mL of a 10% solution of citric acid is added. The organic layeris separated, dried and the solvent removed in vacuum to produce thetitle compound as a semi crystalline solid.

EXAMPLE 9 Preparation of(2S,5S,7S)-5-tert-butoxycarbonylamino-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-8-methyl-4-oxo-nonanoicacid

A solution of 10.0 g of(2S,5S,7S)-5-tert-butoxycarbonylamino-3-ethoxycarbonyl-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-8-methyl-4-oxo-3-propoxycarbonyl-nonanoicacid ethyl ester in 20 mL of ethanol is treated with 25 mL of a 37%solution of sodium hydroxide at room temperature. The reaction mixtureis stirred for 24 hours at room temperature and the ethanol removed bydistillation in vacuum. The residue is extracted twice with 25 mL ofdichloromethane. The pH of the aqueous layer is carefully adjusted to2.5 with 2 N hydrochloric acid at 0° C., the reaction mixture is thenstirred for 16 hours and extracted 4 times with 50 mL ofdichloromethane. The organic layer is dried and the solvent removed togive the title compound as an oil.

EXAMPLE 10 Preparation of{(1S,3S)-1-((2S,4S)-4-isopropyl-5-oxo-tetrahydrofuran-2-yl)-3-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-4-methyl-pentylycarbamicacid tert-butyl ester

A solution of 5.51 g of(2S,5S,7S)-5-tert-butoxycarbonylamino-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-8-methyl-4-oxo-nonanoicacid in 25 mL of tetrahydrofuran is cooled to −30° C. and 10 mL of a 1.0M solution of K-selectride in tetrahydrofuran is added dropwise within30 minutes. The mixture is stirred for 2 hours at 30° C. and warmed to0° C. and stirred for 16 hours. The reaction mixture is quenched with 50mL of 1.0 M hydrochloric acid and extracted three times with 100 mL ofdichloromethane. The organic layer is dried and the solvent is removedto give the title compound as a semi solid.

EXAMPLE 11 Preparation of aliskiren via((1S,2S,4S)-4-(2-carbamoyl-2-methylpropyl-carbamoyl)-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methylbutyl}-5-methylhexyl)-carbamicacid tert-butyl ester

Route A:

A solution of compound (XIa), 3-amino-2,2-dimethylpropionamide and2-hydroxypyridine in tert-butylmethyl ether containing triethylamine isstirred for 18 hours at 83° C. The reaction mixture is then cooled toroom temperature and diluted with toluene and washed with 10% aqueoussodium hydrogen sulphate solution. The organic phase is separated andwashed with water, and the solvent is removed in vacuum to give an oil.This oil is suspended in hexane and stirred. The solid is removed byfiltration and the hexane removed in vacuum to give((1S,2S,4S)-4-(2-carbamoyl-2-methylpropylcarbamoyl)-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methylbutyl}-5-methylhexylycarbamicacid tert-butyl ester, compound (XIb), as a foam.

Compound of formula (XIb) is dissolved in a solution of trifluoroaceticacid in methylene chloride at room temperature. The reaction mixture isstirred for 2 hours and the pH adjusted to 10 with 37% sodium hydroxidesolution. The aqueous phase is extracted three times with 100 mL ofdichloromethane. (for characterization see e.g. EP 0 678 503, Example137).

From the free compound or the hydrochloride salt obtainable, for examplethe hemifumarate salt of the title compound can be prepared, for exampleas described in U.S. Pat. No. 6,730,798, example J1 (comprising mixingwith fumaric acid, dissolution in ethanol, filtration, evaporation ofthe obtained solution, re-dissolving of the residue in acetonitrile,inoculation with a small amount of the title compound's hemifumaratesalt and isolation of the precipitating material), incorporated byreference herein especially with regard to this salt formation reaction.

Route B: From compound of formula (Xa) via((1S,2S)-4-(2-carbamoyl-2-methylpropylcarbamoyl)-1-{(S)-2-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-5-methyl-2-oxo-hexyl)-carbamicacid tert-butyl ester

Compound of formula (Xa) is converted to the amide (Xb) by standardpeptide coupling methods. Reduction as above.). Experimental details canbe found in Houben-Weyl, Methoden der Organische Chemie, 4^(th) Ed,Synthese von Peptiden 1.

Alternative Route to Compounds of Formula (XI) as Outlined in Scheme 4

Step A0){(1S,3S)-1-Formyl-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-carbamicacid tert-butyl ester (XIVa)

The N-Boc-protected alcohol (VIa) is selectively oxidized to thecorresponding aldehyde (XIVa) using the following literature methods: a)F. Montanari et al., J.O.C., 54, 2970 (1989) or b) Review: H. van Bekkumet al., Synthesis 1153 (1996).

Step A)4S,5S,7S)-5-tert-Butoxycarbonylamino-4-hydroxy-7-(4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-non-2-ynoicacid ethyl ester (XVa)

To a 110 mL of a tetrahydrofuran solution of the lithium salt ofpropiolic acid ethyl ester (prepared by treating ethyl propiolate [12.27g] with a molar equivalent of LDA and stirred for 30 minutes to ensurecomplete conversion) at −78° C. is added slowly a solution of thealdehyde (31 g, 70.8 mmol) in 60 mL of tetrahydrofuran. The reactionmixture is stirred for a further 60 minutes and quenched by slowaddition of glacial acetic acid. The solvent is removed and the residuedissolved in methylene chloride and the resulting solution was washedtwice with 200 mL of water. The aqueous phases are re-extracted with afurther 200 mL of methylene chloride and the organic phases are combinedand the solvent removed. The residue is re-dissolved in ethyl acetateand filtered through a bed of silica gel eluting with ethyl acetate. Theproduct containing fractions are combined and the solvent removed invacuum to give 31.4 g of the acetylenic alcohol as a red oil.

¹H-NMR (CDCl₃): 6.8-6.65 (3H, m, Ph), 4.71(1H, Brd, OH), 4.42(1H, Brd,CHNH), 4.30-4.05(4H, m, 2×CH₂), 3.81(3H, s, MeO), 3.70(1H,m, CHOH),3.57(2H, m, CH₂O), 3.35(3H, s, MeO), 2.50(1.5H, m, CHPh and part of a CHsignal), 2.10(2.5H, CH₂ and part of a CH signal), 1.80-1.20(16H, m),1.85(6H, d, iPr).

B)(4S,5S,7S)-5-tert-Butoxycarbonylamino-4-hydroxy-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ethyl ester (XVIa)

To a solution of the acetylene (14 g) in 350 mL of tetrahydrofuran isadded platinum oxide (1.7 g). The resulting suspension is placed underan atmosphere of hydrogen and stirred for 2 hours 20 minutes at normalpressure. The suspension is filtered and the solvent removed to give 31g of a colourless oil which is used without further purification in thenext step (below).

C)[(1S,3S)-3-[4-Methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-1-((S)-5-oxo-tetrahydro-furan-2-yl)-pentyl]-carbamicacid tert-butyl ester (XVIIa)

The hydrogenation product from above (31 g) is dissolved in 50 mL oftoluene and glacial acetic acid (16 mL) is added. The mixture is heatedbetween 95-100° C. for 2 hours. The reaction mixture is cooled and thesolvent is removed in vacuum. The residue is dissolved in 200 mL oftoluene and diluted with 100 mL of water and 100 mL of saturated aqueoussodium bicarbonate. The mixture is extracted and the organic phaseseparated. The organic phase is re-washed with 100 mL of water. Theaqueous phase is separated and combined with the previous water phases.The combined aqueous phases are re-extracted with a further 200 mL oftoluene and the organic phase separated and combined with the previousorganic phases. The solvent is removed in vacuum to give 27.4 g of ayellow oil. The residue is triturated with 100 mL of isopropanol uponwhich the product began to crystallise. Hexane (200 mL) is added slowlyand the resulting suspension stirred at room temperature for 1 hour. Thesuspension is filtered and the product washed with hexane and dried invacuum to give 14 g of the lactone as a white crystalline solid.

mp. 110° C., [α]_(D)=−10.8° (1% in MeOH)

¹HNMR (DMSO, 120° C.) 6.85-6.79(2H, m, Ph), 6.70(1H, m, Ph), 6.25(1H,Brd, NH), 4.40(1H, m, lactone CH), 4.02(2H, t, CH₂O), 3.75(3H, s, MeO),3.62(1H, m, CHN), 3.30(2H, t, CH₂O), 3.25(3H, s, MeO), 2.60-2.30(4H, m,CH₂CO-lactone and PhCH₂), 2.15(1H, m, CH lactone), 1.95-1.80(3H, m,CH₂+CH lactone), 1.65(2H, m, 2×CH), 1.50(1H, m, CH), 1.40(9H, s, tBu),1.20(1H, m, CH), 1.80(6H, d, 2×iPr).

D)(S)-5-{(1S,3S)-1-Amino-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-dihydro-furan-2-one(XVIIIa)

Lactone as HCl Salt:

A solution of 2.96 g of the lactone from above is dissolved in 10 mL ofethyl acetate and treated with a 1.55 M solution of hydrogen chloridegas in ethyl acetate. The mixture is stirred at room temperature for 3hours. The solvent is removed in vacuum and the residue re-dissolved in16 mL of a 1.55 M solution of hydrogen chloride gas in ethyl acetate andstirred at room temperature for a further 16 hours. The solvent isremoved in vacuum to give 2.5 g of the amine hydrochloride as a yellowfoam.

E)(5S,6S)-5-Hydroxy-6-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benryl]-3-methyl-butyl}-piperidin-2-ane(XIXa)

The amine from above (13.0 g) is dissolved in 40 mL of methanol and 5.69g of triethylamine is added at room temperature. The reaction mixture isstirred for 24 hours at room temperature and the solvent is removed invacuum. The residue is re-dissolved in 100 mL of methylene chloride andthe solution washed with 100 mL of water. The organic phase is driedover sodium sulphate and the solvent removed in vacuum to give 12.08 gof the piperidine-2-one as a yellow foam which is processed furtherwithout purification. ¹HNMR (CDCl₃) 7.29(1H, Brs, NH), 6.85-6.65(3H, m,Ph), 5.45(1H, Brs, OH), 4.10(2H, t, CH₂O), 3.83(4H, m, MeO+CHOH),3.58(2H, t, CH₂O), 3.35(3H, s, MeO), 3.22(1H, Brm, CHNH), 2.71-1.25(12H,m), 0.90(6H, m, 2×iPr).

F)(2S,3S)-3-tert-Butoxycarbonyloxy-2-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-6-oxo-piperidine-1-carboxylicacid tert-butyl ester (XXa)

The piperidine-2-one from above (12.08 g) is dissolved in 20 mL oftetrahydrofuran at room temperature. N,N-dimethylaminopyridine (0.63 g),and triethylamine (5.98 g) are added followed by the addition of 12.89 gof di-tert. butyldicarbonate. The reaction mixture is stirred for 24hours at room temperature and the solvent is removed in vacuum. Theresidue is dissolved in 150 mL of ethyl acetate and washed with 100 mLof a 5% aqueous solution of citric acid. The aqueous phase isre-extracted with 100 mL of ethyl acetate and the combined organicphases washed with 2×100 mL of water. The solvent is removed in vacuumto give 16.95 g of a yellow oil. Chromatography on silica-gel elutingwith a toluene/ethyl acetate (1/1) mixture provided the pure bis-bocderivative which crystallizes on standing at room temperature. Mp.89-90° C., after recrystallisation from EtOAc/c-hexane. [α]_(D)=13.0°(1% in MeOH).

¹HNMR (CDCl₃) 6.85-6.70(3H, m, Ph), 4.93(1H, m, CHOBoc), 4.70(1H, m,CHNHBoc), 4.11(2H, t, CH₂O), 3.83(3H, s, MeO), 3.58(2H, t, CH₂O),3.37(3H, s, MeO), 2.65-2.30(3H, m), 2.18-1.40(6H, m), 1.52(9H, s, tBu),1.48(9H, s, tBu), 0.82(6H, m, 2×iPr).

G)(2S,3S)-3-tert-Butoxycarbonyloxy-5-(1-hydroxy-1-methyl-ethyl)-2-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-6-oxo-piperidine-1-carboxylicacid tert-butyl ester (XXIa)

A solution of the bis-Boc derivative (2.46 g) in 10 mL oftetrahydrofuran is cooled to −78° C. and a solution of lithiumhexamethyldisilazide (5.19 g) in 3 mL of tetrahydrofuran is addeddropwise within 10 minutes. The resulting solution is stirred for 2hours at −78° C. Boron trifluoride diethyletherate (0.705 g) is addedfollowed by 1.93 g of acetone dissolved in 3 mL of tetrahydrofuran. Themixture is stirred for 1 hour at −78° C. and a further 0.12 g of borontrifluoride diethyletherate is added and stirring is continued for 24hours at −78° C. After this time 100 mL of a pH17.0 buffer solution wasadded rapidly whereby the temperature rose to 0° C. The mixture isdiluted with a further 60 mL of the pH 7.0 buffer solution and 200 mL ofethyl acetate. The aqueous phase is extracted and the organic phaseseparated. The aqueous phase is re-extracted with 100 mL of ethylacetate and the organic phase separated. The organic phases are combinedand the solvent removed in vacuum. The residue crystallised. The solidis suspended in 25 mL of hexane and stirred overnight at 0° C.Filtration of the solid and washing with hexane provided 2.37 g of thedesired compound.

Mp. 118-119° C., after recrystallisation from EtOAc/hexane.[α]_(D)=34.8° (1% in MeOH).

¹HNMR (CDCl₃) 6.80-6.65(3H, m, Ph), 4.95-4.80(2H, m, OH+CHOBoc),4.50(1H, m, CHNHBoc), 4.11(2H, t, CH₂O), 3.83(3H, s, MeO), 3.56(2H, t,CH₂O), 3.35(3H, s, MeO), 2.70-2.38(3H, m), 2.20-1.60(6H, m), 1.52(9H, s,tBu), 1.45(9H, s, tBu), 1.25(3H, s, Me), 1.18(3H, s, Me), 0.85(6H, m,2×iPr).

H)(2S,3S)-3-tert-Butoxycarbonyloxy-5-isopropenyl-2-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-6-oxo-piperidine-1-carboxylicacid tert-butyl ester (XXIIa)

A solution of the tertiary alcohol from above (2.786 g) in 30 mL ofmethylene chloride is cooled to −5° C. At this temperature is addedtriethylamine (4.33 g) followed by dropwise addition of a solution ofmethanesulphonyl chloride (2.45 g) in 7 mL of methylene chloride within20 minutes. The reaction mixture is stirred for 60 minutes at −5° C. andquenched with 20 mL of pH 3.0 buffer solution, 30 mL of 10% aqueouscitric acid and 50 mL of saturated aqueous sodium bicarbonate solution.The organic phase is separated and washed twice with 100 mL of water.The combined aqueous washings are re-extracted with 100 mL of methylenechloride and the organic phases combined. Removal of the solvent invacuum produced 3.41 g of the crude product as an oil. Chromatography onsilica-gel, eluting with a toluene/ethyl acetate mixture (9/1) gave 2.26g of the pure desired product.

¹HNMR (CDCl₃) 6.85-6.65(3H, m, Ph), 5.10-4.88(2H, m, CH₂═C CHOBoc),4.64(1H, m, CHNHBoc), 4.11(2H, t, CH₂O), 3.83(3H, s, MeO), 3.58(2H, t,CH₂O), 3.35(3H, s, MeO), 3.2(1H, t, CH), 2.60-2.30(2H, m PhCH₂),2.10(2H, m), 1.80(3H, s, Me), 1.79-1.60(3H, m), 1.52(9H, s, tBu),1.48(9H, s, tBu), 0.81(6H, m, 2×iPr).

I)(2S,3S)-3-tert-Butoxycarbonyloxy-5-isopropylidene-2-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-6-oxo-piperidine-1-carboxylicacid tert-butyl ester (XXIIIa)

A solution of the compound with the exocyclic double bond (1.95 g) in 25mL of ethyl acetate is treated with 1 g of active charcoal and 0.3 g oftriethylamine. The mixture was stirred for 2 hours at room temperatureand filtered. The solid is washed with 10 mL of ethyl acetate and thesolvent is removed in vacuum to produce 1.90 g of a semi-solid. This wascrystallised from hexane to give 1.257 g of pure product.

¹HNMR (CDCl₃) 6.80-6.65(3H, m, Ph), 4.95(2H, m, CHOBoc), 4.75(1H, m,CHNHBoc), 4.10(2H, t, CH₂O), 3.83(3H, s, MeO), 3.58(2H, t, CH₂O),3.35(3H, s, MeO), 2.85-2.55(2H, m PhCH₂), 2.45-2.30(2H, m), 2.10(5H, m),1.73-1.40(23H, m), 0.81(3H, d, iPr), 0.71(3H, d, iPr).

J)(2S,3S,5S)-3-tert-Butoxycarbonyloxy-5-isopropyl-2-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-6-oxo-piperidine-1-carboxylicacid tert-butyl ester (XXIVa)

A solution of the olefin from above (0.38 g) in 10 mL of ethyl acetateis treated with 0.3 g of Pt/C-5%. Triethylamine (0.086 g) is added andthe suspension placed under an atmosphere of hydrogen. The temperatureis increased to 50° C. and the pressure to 5 bar. The reaction mixtureis stirred under these conditions for 24 hours, cooled to roomtemperature and the catalyst removed by filtration. The solvent isremoved in vacuum and the residue purified by chromatography oversilica-gel, eluting with toluene/ethyl acetate/3:1). The productcontaining fractions are combined and the solvent removed to give thedesired compound (0.3 g) as an oil.

¹HNMR (CDCl₃) 6.85-6.70(3H, m, Ph), 5.00(1H, m, CHOBoc), 4.65(1H, m,CHNHBoc), 4.15(2H, t, CH₂O), 3.83(3H, s, MeO), 3.58(2H, t, CH₂O),3.35(3H, s, MeO), 2.60-2.40(2H, m PhCH₂), 2.10(2H, m, CH₂),2.00-1.65(4H, m), 1.58-1.30(20H, m), 0.85(6H, m, 2×Me), 0.75(6H, m,2×Me).

K){(1S,3S)-1-((2S,4S)-4-Isopropyl-5-oxo-tetrahydro-furan-2-yl)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-carbamicacid tert-butyl ester (XIa)

A solution of the piperidinone (0.28 g) in 3 mL of tetrahydrofuran istreated, at room temperature, with 1 mL of a 2.0M solution of sodiumhydroxide in water. Benzyltriethylammonium chloride (2 mg) is added andthe mixture stirred at 40° C. for 5 hours. Ethanol (1 mL) is added andstirring continued at 40° C. for 24 hours. The mixture is then cooled toroom temperature and glacial acetic acid (2 mL) is added. The acidmixture is extracted into a toluene/water mixture and the organic phaseseparated. The solvent is removed in vacuum to give an oil. This oil isre-dissolved in 5 mL of glacial acetic acid and stirred for 24 hours at100° C. The acetic acid is then removed in vacuum and the residuepurified by preparative thin layer chromatography, eluting with ethylacetate/hexane, 1/1. This provided 0,0476 g of the desired product.

¹HNMR (CDCl₃) 6.81-6.70(3H, m, Ph), 4.40(1H, m, CHO-Lactone ring),4.10(2H, t, CH₂O), 3.85-3.79(4H, m, MeO+CHNBoc), 3.58(2H, t, CH₂O),3.35(3H, s, MeO), 2.85-2.55(2H, m PhCH₂), 2.65(1H, dd, PhCH), 2.55(1H,m, CHCO-lactone), 2.40(1H, dd, PhCH), 2.12-2.05(5H, m), 1.70-1.30(13H,m), 1.05(3H, d, Me), 0.95(3H, d, Me), 0.85(6H, d, iPr).

[α]_(D)=−6.1° (c=3 in CH₂Cl₂).

Examples for the Preparation of Compound (VIIIb)

Preparation of 2-(R)-(4-Nosyloxy)-isovalerianic acid methylester(R₄=i-propyl, R₉=methyl)

43.6 g (330 mmol) 2-(R)-hydroxy-isovalerianic acid methylester, whichcan be prepared according to a literature procedure (Lit.: 1a-1c) aredissolved in 50 ml of dichloromethane. To the solution is added 38.4 g(379.4 mmol) of triethylamine and 4.0 g (33 mmol) of dime-thylaminopyridine. After cooling to 0° C. a solution of 80.42 (362.9 mmol)4-nitrobenzene-sulfonylchloride in 250 ml di-chloromethane is addedslowly under stirring during 45 minutes. After stirring over night thereaction mixture is cooled to 0° C. and 25 ml 2N hydrochloric acid isadded to adjust the pH to 3.5. The aqueous phase is extracted with 2×10ml of dichloromethane and the combined organic phase is washed with 100ml of water. The organic phase is evaporated in vacuum. The resultingorange oil is re-dissolved in 200 ml of toluene and extracted with 30 ml1N hydrochloric acid, 50 ml of brine, 50 ml of saturated sodiumbicarbonate solution and again with brine. The organic phase is thenfiltered via a pad of silica gel and the product is eluted with around 2liters of toluene. The collected product fractions are evaporated invacuum to give an orange oil (91.5 g) which crystallizes after seedingand cooling in the refrigerator. The resulting crystals are trituratedwith pentane and are filtered and washed with 2×50 ml of pentane to giveafter drying 84.3 g of crystalline product. m.p.: 46-48° C.;[α]_(D)=+6.5° (1% CHCl₃)

¹H-NMR (CDCl₃): 8.34 (2H, d), 8.08 (2H. d), 4.77 (1H, d), 3.61 (3H, s),2.17-2.24(1H, m), 0.91 (3H, d), 0.86 (3H, d).

-   -   Literature: 1a) Tetrahedron, 46, 6623 (1990)    -   1b) J. Chem. Soc.; Perk. Trans. 1, (12), 1427 (1996)    -   1c) J. Org. Chem., 52, 4978 (1987)

Preparation of [R)-2-Isopropyl-3-methoxycarbonyl-succinic acid dimethylester (R₄=i-propyl, all R₉=methyl)

A 500 ml three necked flask is charged with 16.8 g of sodium hydride(60% in mineral oil), 420 mmol. The NaH is washed 3 times with 20 mlportions of hexane under a flow of argon gas. Then 150 ml of n-dipropylether is added. The reaction mixture is cooled to 0° C. and 59.45 g (450mmol) of dimethyl malonate, dissolved in 50 ml of n-dipropyl ether isslowly added under stirring. Strong hydrogen evolution and a temperatureincrease is observed. Temperature is kept at 15° C. during addition. Awhite, thick suspension is formed. Additional 50 ml of n-dipropyl etheris added to delute the heterogenous mixture. The reaction temperature isincreased to 50° C. for 2 hours to complete the deprotonation. At thistemperature a solution of the “nosylate”, 47.58 g (150 mmol) in 120 mln-dipropyl ether is added to the heterogenous mixture. The very thickbrown suspension is heated at an internal temperature of 85° C. for 24hours. After that time complete conversion of the nosylate is observed(GC). The reaction mixture is cooled to room temperature and quenched bycareful addition to a mixture of 150 ml toluene and 150 ml water. Theaqueous phase is extracted two times with 50 ml of toluene. The organicphases are combined and washed with 2×50 ml sodium bicarbonate, 2×50 ml2N hydrochloric acid, and finally with 3×50 ml water to give afterevaporation of the solvents in vacuum 48.2 g of a yellow oil. This oilis triturated with 150 ml hexane under stirring to give afterevaporation 28 g of a slightly yellow oil. This oil is filtered througha pad of silica gel with a mixture of toluene/ethyl acetate (9:1).Chromatography fractions which contain pure product are combined and thesolvent is evaporated in vacuum to give an almost colourless oil whichcrystallises in the refrigerator over night. The crystalls aretriturated with cold pentane, filtered and washed with small amounts ofpentane to give after drying in vacuum 9.5 g of almost white product.

mp.: 45-48° X, [α]_(D)=+62.5° (1% in MeOH)

¹H-NMR (CDCl₃): 3.87 (1H, d), 3.74 (3H, s), 3.70 (3H, s), 3.68 (3H, s),3.12 (1H, dd), 1.78-1.85 (1H, m), 1.01 (3H, d), 0.88 (3H, d).

1-16. (canceled)
 17. A compound of the formula

wherein R₃ is branched C₃₋₆alkyl, preferably i-propyl, and R₆ isC₁₋₂₀alkyl, C₃₋₁₂cycloalkyl, C₃₋₁₂cycloalkyl-C₁₋₆alkyl, C₆₋₁₀aryl orC₆₋₁₀aryl-C₁₋₆alkyl, preferably C₁₋₄alkyl, most preferably methyl orethyl; and wherein the phenyl ring shown in the structure may besubstituted by one or more, e.g. two or three, residues e.g. thoseselected from the group consisting of C₁-C₇-alkyl, hydroxy,C₁-C₇-alkoxy, C₂-C₈-alkanoyl-oxy, halogen, nitro, cyano, and CF₃.
 18. Acompound of the formula

wherein R3 is branched C3-6alkyl, preferably i-propyl. 19-43. (canceled)